The relevance of the CD4/CD8 ratio in the ART era
1 June 2014. Related: Basic science.
Richard Jefferys, TAG
An inversion of the normal ratio between CD4 and CD8 T cells was noted in the very first case reports of individuals with AIDS, before HIV was even identified.
Although a number of studies subsequently reported an association between the CD4/CD8 ratio and risk of disease progression, CD4 T cell counts were more extensively researched and became the most commonly used surrogate marker of immune system health in HIV-positive people. In recent years, data has emerged from cohort studies of very elderly HIV-negative people indicating that, in this population, the CD4/CD8 ratio is a strong predictor of the risk of aging-associated diseases and mortality. This new information prompted the research group of Sergio Serrano-Villar at the University Hospital Ramón y Cajal in Madrid to evaluate whether measurement of the CD4/CD8 ratio may provide information about the risk of morbidity and mortality in HIV-positive people in the current era of antiretroviral therapy (ART).
Last year, Serrano-Villar and colleagues published preliminary studies showing associations between the CD4/CD8 ratio and levels of immune activation  and markers of immune system aging  (immunosenescence) in HIV infection. In two new papers published in HIV Medicine and PLoS One, they now extend these findings and report statistically significant associations between the CD4/CD8 ratio and markers of age-associated disease and the clinical outcomes of non-AIDS-related morbidity and mortality in HIV-positive people. [3, 4]
The PLoS One study assesses the link between the CD4/CD8 ratio and several dissimilar non-AIDS diseases in people on ART, and reports a significant association in each case. Separate analyses of participants with low CD4 nadirs (<200 cells) and those with good CD4 recovery on ART (to >350 cells) find that CD4/CD8 ratios remain independently associated with non-AIDS events in each subgroup.
In discussing the implications of their findings, the researchers write: “patients with failure to increase the CD4/CD8 ratio despite achieving full immunovirological response to ART might benefit from screening programs and aggressive management of concomitant risk factors for age-associated disease.” They also note that, since there appears to be a relationship between immune activation and the CD4/CD8 ratio, such individuals may be prime candidates for inclusion in clinical trials of interventions that aim to reduce immune activation and associated adverse clinical outcomes. However, several limitations to the study are acknowledged, and the authors stress that: “before using the CD4/CD8 ratio as a surrogate of serious non-AIDS-related illnesses, these results should be reproduced in larger and prospective studies.”
As it currently stands, there are very few reports of therapies capable of improving low CD4/CD8 ratios in HIV-positive people on ART. IL-7 increases both CD4 and CD8 T cell numbers, and according to a new study published in PLoS Pathogens, may reduce markers of inflammation, but the clinical impact of this cytokine has yet to be evaluated. 
A further complication is that the company behind IL-7, Cytheris, recently went bankrupt, leaving the rights to its development for HIV in the hands of the French Agence Nationale de Recherche sur le SIDA (ANRS) and a small biotech named Cognate Biosciences. SB-728-T, a gene therapy under development by Sangamo Biosciences, has been reported to significantly improve CD4/CD8 ratios in people on ART, but the duration of the effect is unclear and the company appears uninterested in developing the approach for people with suboptimal immune reconstitution (their focus is on attempting to achieve control of HIV replication after ART interruption). The therapy is also complex to administer because it involves the extraction, expansion and genetic modification of CD4 T cells, followed by reinfusion. A letter from TAG and many other community activists and organizations asking the company to continue to study the potential of SB-728-T to promote immune reconstitution fell on deaf ears. 
Although not directly connected to the work of Sergio Serrano-Villar and colleagues, another study on the topic of the CD4/CD8 ratio in HIV infection was published online by the Journal of Immunology this past Monday. 
Marcus Buggert and a Swedish research team used a bioinformatics approach to explore the connections between several of the laboratory measures used to monitor HIV disease progression (including CD4 count and CD4/CD8 ratio) and a large suite of T cell markers that are perturbed by HIV infection (including activation, exhaustion and immunosenescence markers). Focusing primarily on untreated HIV infection, the researchers find that the CD4/CD8 ratio is the best predictor of the combined pathological changes to the T cell immune system that occur in HIV-positive people compared to uninfected controls. The paper concludes: “these findings are of particular interest to future therapy or cure studies, in which simple measurements are required to monitor ongoing pathological events of the T cell repertoire in HIV-infected subjects.”
TAG Basic Science Blog. The Relevance of the CD4/CD8 Ratio in the Antiretroviral Therapy Era. (05 February 2014).
- Serrano-Villar S et al. The CD4/CD8 ratio in HIV-infected subjects is independently associated with T-cell activation despite long-term viral suppression. Journal of Infection 66(1):;57-66 (January 2013).
- Serrano-Villar S et al. The CD4/CD8 ratio as a marker T-cell activation, senescence and activation/exhaustion in treated HIV-infected children and young adults. AIDS 27(9);1513-1516. (1 June 2013). doi: 10.1097/QAD.0b013e32835faa72.
- Serrano-Villar S et al. The CD4:CD8 ratio is associated with markers of age-associated disease in virally suppressed HIV-infected patients with immunological recovery. HIV Med. 2014 Jan;15(1):40-9. doi: 10.1111/hiv.12081. Epub 2013 Sep 6.
- Serrano-Villar S et al. Increased risk of serious non-AIDS-related events in HIV-infected subjects on antiretroviral therapy associated with a low CD4/CD8 ratio. PLoS ONE 9(1): e85798. doi:10.1371/journal.pone.0085798. (30 January 2014).
- Sereti I et al. Decreases in colonic and systemic inflammation in chronic HIV infection after IL-7 administration. PLoS Pathogens, 30 January 2014. doi: 10.1371/journal.ppat.1003890.
- TAG et al. Letter to Sangamo on its development for zinc finger functional cure. (12 January 2102).
- Buggert M et al. Multiparametric bioinformatics distinguish the CD4/CD8 ratio as a suitable laboratory predictor of combined T cell pathogenesis in HIV infection. The Journal of Immunology. 03 February 2014. doi: 10.4049/ jimmunol.1302596.